The important role of phospholipase A.sub.2 in the biosynthesis of prostaglandins and leukotrienes indicates that inhibitors of phospholipase A.sub.2 may be valuable therapeutic agents having wide applicability in inflammatory and/or allergic conditions in mammals. Although some currently available anti-inflammatory agents show activity against phospholipase A.sub.2 or other enzymes of the "arachidonic acid cascade", there is a continuing need for safer and more effective drugs capable of treating inflammatory and/or allergic diseases.
The rationale for, and reports of, production of effective inhibitors of phospholipase A.sub.2 as potential anti-inflammatory drugs have been outlined extensively in a recent review (see Wilkerson, Drugs of the Future, 15(2), 140 (1990).
In U.S. Pat. No. 4,371,543, issued Jun. 5, 1981 to G. C. Rovnyhak, there are disclosed bis-amide indene ketone compounds of the formula: ##STR2## where Q is a group of the formula: ##STR3## These compounds were claimed as anti-inflammatory agents.
German Patent 2,462,380, issued Dec. 20, 1973, discloses a process to produce an anti-inflammatory benzylidene indene acetic acid claimed in U.S. Pat. No. 3,654,349 of the formula: ##STR4## Also therein claimed as anti-inflammatory intermediates are compounds of the formula: ##STR5## wherein R.sup.1 is SCH.sub.3 or S(O)CH.sub.3.
U.S. Pat. No. 3,681,436, issued Aug. 1, 1972 to D. M. Lynch and J. W. Cole, discloses substituted 1-benzylindanes of the formula: ##STR6## wherein R is OH, methoxy or acetoxy, R.sup.1 is H or R and R.sup.2 is H, methyl or acetyl. These compounds have been found to inhibit the metabolic function of female reproductive organs in warm-blooded animals.
U.S. Pat. No. 4,013,682, issued Mar. 22, 1977 to H. J. Panneman, discloses compounds of the formula: ##STR7## These compounds possess vasodilatory and antihypertensive properties.
U.S. Pat. No. 4,528,508, issued Jul. 9, 1985 to E. Plummer, disclosed indanes of the formula: ##STR8##
W. C. Ripka, W. J. Sipio, and W. G. Galbraith, in Journal of Cellular Biochemistry, 40, 279-286 (1989), describe a compound of the formula: ##STR9## which is claimed to possess inhibitory activity against porcine pancreatic phospolipase A.sub.2.
Phospholipase A.sub.2 (PLA.sub.2) acts to release arachidonic acid from phospholipids. Once released, arachidonic acid is rapidly metabolized by a variety of enzymes of the "arachidonic acid cascade." The products of the arachidonic acid cascade include prostaglandins, leukotrienes, and related compounds. These compounds exhibit a remarkably broad spectrum of biological activity, and inhibition of their biosynthesis is recognized as a valuable mechanism for production of anti-inflammatory effects.
Both prostaglandins and leukotrienes are believed to have important functions as mediators of inflammation and currently available drugs which inhibit their production are of significant therapeutic value in man and other mammals. Nonsteroidal anti-inflammatory agents such as the salicylates act as inhibitors of prostaglandin synthesis from arachidonic acid by inhibiting the cyclooxygenases. This inhibition of prostaglandin synthesis is believed to be the basis for many of the therapeutic effects of the aspirin-like drugs. The anti-inflammatory activity of the glucocorticosteroids, on the other hand, is believed to be at least partly due to their ability to induce the biosynthesis of a PLA.sub.2 inhibitor protein, thereby diminishing the release of arachidonic acid from phospholipids. By decreasing concentrations of arachidonic acid, the substrate for the entire arachidonic acid cascade, production of leukotrienes as well as prostaglandins can be decreased.
Many diseases and conditions in man and other mammals have inflammatory and/or allergic components believed to be mediated by PLA.sub.2, e.g., rheumatoid arthritis and other rheumatic disorders, various collagen diseases, dermatoses, psoriasis, hypersensitivity and immune reactions, bronchospastic diseases such as asthma, and disorders of platelet aggregation. Because the compounds of this invention have shown activity as PLA.sub.2 inhibitors, valuable pharmacological activity in these and other diseases or conditions mediated by the various products of the arachidonic acid cascade is to be expected.